FOXP2 down expression is associated with executive dysfunctions and electrophysiological abnormalities of brain in Autism spectrum disorder; a neuroimaging genetic study.

Background and aims: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by language impairment, and challenges with social interaction, communication, and repetitive behaviors. Although genetics are a primary cause of ASD, the exact genes and molecular mechanisms involved in its pathogenesis are not completely clear. The FOXP2 gene encodes a transcription factor that is known for its major role in language development and severe speech problems. The present study aimed to evaluate the role of FOXP2 in ASD etiology, executive functions, and brain activities. Methods: In the present study, we recruited 450 children with ASD and 490 neurotypical control children. Three domains of executive functions (working memory, response inhibition, and vigilance) were assessed. In addition, five-minute eyes closed electroencephalography was obtained from some of the children with ASD and neurotypical children. DNA sequence and expression level of FOXP2 in blood samples of children with ASD and the control group were evaluated by using sequencing and Real-time PCR, respectively. Results: The results showed no mutations but a significant down expression of FOXP2 genes in children with ASD vs. neurotypical children. Several cognitive and executive function deficiencies were detected in children with ASD. Low alpha and gamma bands in the frontal lobe and high theta bands in the occipital lobe were revealed in children with ASD. We also found several correlations between FOXP2 expression levels and clinical assessments. Conclusions: Our finding revealed the down expression of FOXP2, which could be considered as a biomarker for ASD as well as cognitive and executive dysfunction. Based on brain mapping data, FOXP2 may be related to the theta wave abnormality of children with ASD. FOXP2 may be considered a target of novel treatment to improve memory and executive functions. Implications: Our findings highlight the role of FOXP2 mRNA level in ASD etiology, executive functions, and brain wave frequencies.

Solid lipid nanoparticles: a promising tool for insulin delivery.

INTRODUCTION: Insulin plays a critical role in metabolism modulation including carbohydrate, lipid, and protein metabolism. There is room to improve insulin delivery but optimizing the best carrier remains challenging. Traditional and conventional approaches for insulin delivery do not emulate the normal fate of insulin release in the body. Despite extensive research attempts to overcome this and other challenges, the goal of achieving optimal insulin delivery that emulates the natural system remains unresolved. AREAS COVERED: Solid Lipid Nanoparticles (SLNs) may provide a solution, because they are nontoxic, biocompatible, and straightforward to formulate thus providing a promising platform for achieving targeted and controlled delivery of various therapeutic agents. This review aims to provide an overview on the suitability and application of SLNs for insulin delivery. A special emphasis is placed on the biopharmaceutical aspects of insulin loaded SLNs which have not been explored in detail to date. EXPERT OPINION: SLNs have proven to be safe and versatile drug delivery systems suitable for insulin delivery and capable of improving the efficacy and pharmacokinetic profile of encapsulated insulin. There is still some work to be done to fully explore SLNs' true potential as drug delivery and specifically insulin delivery vehicles suitable for clinical use.

The Impacts of PLGA/PEG Triblock Copolymers with Variable Molecular Weights on the Sustained Release of Buprenorphine.

OBJECTIVE: Current in-situ injectable implants of buprenorphine (BP) such as Sublocade® consist of N-methyl-2-pyrrolidone (NMP)-dissolved PLGA. To control the initial burst release of Sublocade® during the first 24 hours after injection, we here used a BP in-situ forming composite (ISFC) employing different molecular weights of PLGA-PEG-PLGA triblock. METHODS: The triblock was synthesized by Ring-Opening Polymerization (ROP) using PEG molecules with weights of 1500, 3000, and 4000 Da via the melting method. The specifications of the triblocks were evaluated by 1H-NMR, FTIR, GPC, and DSC. The sol-gel, gel-precipitate temperatures, in-vitro release, and composites' morphology, degradation, and toxicity were assessed for determining the features of ISFC 1500, ISFC 3000, and ISFC 4000 formulations. ROP was performed successfully via the melting method. The yields of all polymerization reactions were greater than 83.4%. RESULTS: The PEG 1500 triblock showed both sol-gel and gel-precipitate temperatures, but PEG 3000 and 4000 only showed a sol-precipitate temperature. The values of initial burst release of BP from ISFC 1500, ISFC 3000, and ISFC 4000 were 6.52 ± 0.22%, 12.39 ± 0.61%, and 15.80 ± 0.98%, respectively. BP release from the ISFCs wascompleted over three weeks for ISFC 1500 and 10 days for ISFC 3000 and ISFC 4000. The composites containing PEG 3000 and PEG 4000 were more spongy and porous than PEG 1500. The ISFC 1500 delivered a higher cell viability (95.17 ± 1.15%) compared with ISFC 3000 (86.37 ± 2.25%) and ISFC 4000 (79.70 ± 3.77%). CONCLUSION: These results indicated that ISFC 1500 wasbiocompatible and delivered suitable early initial burst reactions compared with ISFC 3000 and 4000 and might be a good candidate for preparing sustained-release formulation of BP.

Immunological Assessment of Chitosan or Trimethyl Chitosan-Coated PLGA Nanospheres Containing Fusion Antigen as the Novel Vaccine Candidates Against Tuberculosis.

The crucial challenge in tuberculosis (TB) as a chronic infectious disease is to present a novel vaccine candidate that improves current vaccination and provides efficient protection in individuals. The present study aimed to evaluate the immune efficacy of multi-subunit vaccines containing chitosan (CHT)- or trimethyl chitosan (TMC)-coated PLGA nanospheres to stimulate cell-mediated and mucosal responses against Mycobacterium Tuberculosis (Mtb) in an animal model. The surface-modified PLGA nanoparticles (NPs) containing tri-fusion protein from three Mtb antigens were produced by the double emulsion technique. The subcutaneously or nasally administered PLGA vaccines in the absence or presence of BCG were assessed to compare the levels of mucosal IgA, IgG1, and IgG2a production as well as secretion of IFN-γ, IL-17, IL-4, and TGF-ß cytokines. According to the release profile, the tri-fusion encapsulated in modified PLGA NPs demonstrated a biphasic release profile including initial burst release on the first day and sustained release within 18 days. All designed PLGA vaccines induced a shift of Th1/Th2 balance toward Th1-dominant response. Although immunized mice through subcutaneous injection elicited higher cell-mediated responses relative to the nasal vaccination, the intranasally administered groups stimulated robust mucosal IgA immunity. The modified PLGA NPs using TMC cationic polymer were more efficient to elevate Th1 and mucosal responses in comparison with the CHT-coated PLGA nanospheres. Our findings highlighted that the tri-fusion loaded in TMC-PLGA NPs may represent an efficient prophylactic vaccine and can be considered as a novel candidate against TB.

Encapsulation and Release of Doxorubicin from TiO2 Nanotubes: Experiment, Density Functional Theory Calculations, and Molecular Dynamics Simulation.

Titanium dioxide (TiO2) nanotubes are attractive materials for drug-delivery systems because of their biocompatibility, chemical stability, and simple preparation. In this study, we loaded TiO2 nanotubes with anticancer drug doxorubicin (DOX) experimentally and in all-atom molecular dynamics (MD) simulations. The release of doxorubicin from the nanotubes was studied by high-performance liquid chromatography (HPLC) and confocal Raman spectroscopy, and drug-release profiles were evaluated under various conditions. The polyethylene glycol (PEG) coating and capping of the nanotubes led to a marked increase in the water contact angles from about 16 to 33° in keeping with reduced wettability. The capping retarded the release rate without decreasing the overall release amount. The MD simulations further show that the DOX molecule diffusion coefficients (Di) are in the order of 10-10 m2/s. The DOX molecules show a plethora of short- and long-range H-bonding interactions with TiO2 nanotube walls and water. Calculated radial distribution functions (RDFs) and combined radial/angular distribution functions (CDFs) allowed gauging the strength of these hydrogen bonds. The strength does not fully correlate with the pKa values of DOX atoms which we assign to the confinement of DOX and water in the tubes. The lifetimes of hydrogen bonds between the DOX atoms and water molecules are shorter than that of the DOX...TiO2 interactions, and DOX...DOX aggregation does not play an important role. These results suggest TiO2 nanotubes as promising candidates for controllable drug-delivery systems for DOX or similar antiproliferative molecules.

New insight into electrosynthesis of ordered TiO2 nanotubes in EG-based electrolyte solutions: combined experimental and computational assessment.

To obtain a better understanding of TiO2 nanotube (TiO2-NT) synthesis in different ethylene glycol (EG)-based electrolyte solutions by electrochemical anodization, the primary steps of TiO2-NT formation were studied by experimental techniques. In this regard, three different EG-based electrolyte solutions were used for anodic oxidation of titanium foil. The first electrolyte solution contains conventional ammonium fluoride (NH4F) dissolved in EG/water (98 : 2 v/v). In the second one, Ti foil anodization is performed in an electrolyte solution containing the 1-butyl-3-methyl-imidazolium tetrafluoroborate (Bmim-BF4) ionic liquid. Finally, the fluorine-containing species was replaced by the 1-butyl-3-methyl-imidazolium chloride (Bmim-Cl) ionic liquid. The results indicate that the TiO2-NTs did not form by anodization in the EG/H2O/Bmim-Cl electrolyte solution at 60 V. Interestingly, this electrolyte solution is less viscous than the fluorine-containing electrolyte solutions. In addition, we report a detailed study on the structural arrangement of electrolyte solution components near the solid surfaces using molecular dynamics (MD) simulation methods to reveal the factors governing the difference of the ionic species distribution. The MD results elucidate the role of the ionic constituents in the length of the nanotube arrays at a certain anodization condition. Furthermore, as reported herein for the first time, the lifetimes of ion-ion contacts and the interactions of ionic species with TiO2 walls have a substantial effect on the resulting nanotubes. These characteristics are analyzed by using radial distribution functions, density profiles, distance analysis, time correlation functions, and mean-square-displacements, complemented by DFT calculations.

In-vitro Release Evaluation of Growth Hormone from an Injectable In-Situ Forming Gel Using PCL-PEG-PCL Thermosensitive Triblock.

OBJECTIVE: An injectable long acting In-Situ Forming Gel (ISFG) of human Growth Hormone (hGH) was prepared by using triblock PCL-PEG-PCL (Mw 1500-1500-1500). Ring-Opening Polymerization (ROP) of triblock using microwave was applied. METHODS: The BCA protein assay Kit was used to determine the concentration of hGH in the in-vitro release medium. Finally, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis (SDS-PAGE) tests and Circular Dichroism (CD) spectrum were done to approve the stability of released hGH. The result of ROP demonstrated that the proportion of PCL to PEG accorded with the initial molar ratio of the monomers. The cross-section of the Surface Electron Microscopy (SEM) indicated the porous framework of the hydrogel could load the drug into its tridimensional matrixes structure. There is the low initial burst release of hGH from the supramolecular hydrogel. RESULTS: The maximum in-vitro release of hGH was 71.2 % ± 1.5 that were due to hGH degrading after this time (21 days). The CD spectrum and SDS-PAGE results confirmed the stability of hGH during invitro release evaluation. CONCLUSION: The results suggest that the sustained-release formulation using PCL-PEG-PCL can be applied to control the release of hGH.

Preparation, in vitro and in vivo evaluation of PLGA/Chitosan based nano-complex as a novel insulin delivery formulation.

The smart self-regulated drug delivery systems for insulin administration are desirable to achieve glycemic control, and decrease the long-term micro- and macro vascular complications. In this study, we developed an injectable nano-complex formulation for closed-loop insulin delivery after subcutaneous administration and release of insulin in response to increased blood glucose levels. The nano-complex was prepared by mixing oppositely charged chitosan and PLGA nanoparticles. PLGA nanoparticles were prepared using double-emulsion solvent diffusion method, and were loaded with glucose oxidase (GOx) and catalase (CAT) enzymes. These negatively charged particles decrease micro-environmental pH, by gluconic acid production in the glucose molecules presence. Positively charged chitosan nanoparticles were prepared using ionic gelation method, and were loaded with insulin. These nanoparticles (NPs) released insulin by dissociation in acidic pH caused by the GOx activity. Following in vitro studies, in vivo evaluation of nano-complex formulations in streptozocin induced diabetic rats showed significant glycemic regulation up to 98 h after subcutaneous administration.

Confinement of aqueous mixtures of ionic liquids between amorphous TiO2 slit nanopores: electrostatic field induction.

Electrostatic potential in the vicinity of the surface is induced when aqueous mixtures of hydrophobic and hydrophilic ionic liquids (ILs) are confined between a slit nanopore of amorphous but not crystalline TiO2 semiconductors. According to our molecular dynamics (MD) simulations, the extent of ion-pairing lifetime under such nanoscale confinement is substantially lower than its value in the bulk. It becomes still lower when aqueous mixtures of ionic liquid electrolytes are used. Ion-ion correlation is broken completely in the confined dilute aqueous electrolyte systems. The anions and cations of the ILs migrate and accumulate at the opposite amorphous TiO2 electrodes that are separated by 10 nm to arrange a nanosize pore. In contrast, we have shown that the electrostatic interactions between the IL ions are dominant when the electrolyte is confined between anatase (101) TiO2. A similar trend is observed for the inorganic electrolyte system. These findings shed light on the design of new cells for electrochemical applications.

The Role of Hydroxychloroquine as a Steroid-sparing Agent in the Treatment of Immune Thrombocytopenia: A Review of the Literature.

Immune Thrombocytopenia (ITP) is an autoimmune disease in which platelet destruction causes thrombocytopenia. Due to the known steroid toxicities, alternative agents have been evaluated for the treatment of these patients. We aimed to review the literature and find evidences regarding the potential benefits of hydroxychloroquine (HCQ) as a steroid-sparing agent in the treatment of ITP. We searched English language articles within Web of Science, PubMed, and Scopus. Cohorts, clinical trials, case reports, conference papers, and letters were included. We excluded papers which either focused on administration of HCQ for non-ITP conditions or studies on other treatment modalities for ITP. In total, 54 ITP cases with either primary or systemic lupus erythematosus (SLE)-associated ITP were included in four studies (SLE-associated ITP; n = 23). All patients have received corticosteroids previously and >90% received other agents with HCQ concomitantly. Overall response was achieved in more than 60% of patients. Sustained response in 18 (33.3%) patients was associated with no treatment or HCQ alone. One of the studies reported a significantly better response in patients with definite SLE compared to those with positive antinuclear antibody and no definite SLE. Similarly, another study found a nonsignificant trend toward better long-term response in patients with definite SLE compared to incomplete SLE. The included articles reported the efficacy of the HCQ with acceptable safety. Available data regarding the use of HCQ for this indication are spare and more studies are needed in ITP with different severity. It seems that HCQ can be considered as an option in the treatment of SLE-associated ITP, and although promising, currently, the place of HCQ in the treatment of ITP continues to evolve.

Anti-invasion Effects of Cannabinoids Agonist and Antagonist on Human Breast Cancer Stem Cells.

Studies show that cancer cell invasion or metastasis is the primary cause of death in malignancies including breast cancer. The existence of cancer stem cells (CSCs) in breast cancer may account for tumor initiation, progression, and metastasis. Recent studies have reported different effects of cannabinoids on cancer cells via CB1 and CB2 cannabinoid receptors. In the present study, the effects of ACEA (a selective CB1 receptor agonist) and AM251 (a selective CB1 antagonist) on CSCs and their parental cells were investigated. Breast CSCs derived from MDA-MB-231 cell line were sorted and characterized with CD44+/CD24-/low/ESA+ phenotype. It was observed that ACEA decreased CD44+/CD24-/low/ESA+ cancer stem cell invasiveness. Conversely, AM251 increased the invasion by more than 20% (at the highest concentrations) in both MDA-MB-231 and CSCs. Our results did not show any correlation between reduced invasion and cytotoxic effects of the drug. Since one of the main cancer recurrence factors is anti-cancer drugs fail to inhibit CSC population, this observation would be useful for cancer treatment.

Synthetic Zeolites as Controlled-Release Delivery Systems for Anti-Inflammatory Drugs.

Scientists have always been trying to use artificial zeolites to make modified-release drug delivery systems in the gastrointestinal tract. An ideal carrier should have the capability to release the drug in the intestine, which is the main area of absorption. Zeolites are mineral aluminosilicate compounds with regular structure and huge porosity, which are available in natural and artificial forms. In this study, soaking, filtration and solvent evaporation methods were used to load the drugs after activation of the zeolites. Weight measurement, spectroscopy FTIR, thermogravimetry and scanning electronic microscope were used to determine drug loading on the systems. Finally, consideration of drug release was made in a simulated gastric fluid and a simulated intestinal fluid for all matrixes (zeolites containing drugs) and drugs without zeolites. Diclofenac sodium (D) and piroxicam (P) were used as the drug models, and zeolites X and Y as the carriers. Drug loading percentage showed that over 90% of drugs were loaded on zeolites. Dissolution tests in stomach pH environment showed that the control samples (drug without zeolite) released considerable amount of drugs (about 90%) within first 15 min when it was about 10-20% for the matrixes. These results are favorable as NSAIDs irritate the stomach wall and it is ideal not to release much drugs in the stomach. Furthermore, release rate of drugs from matrixes has shown slower rate in comparison with control samples in intestine pH environment.

Effects of energy drinks on blood pressure, heart rate, and electrocardiographic parameters: An experimental study on healthy young adults.

OBJECTIVE: To evaluate the effects of the consumption of energy drinks on cardiovascular parameters in a group of healthy young individuals. METHODS: In a quasi-experimental study, 44 healthy adult participants aged between 15 and 30 years were evaluated. The blood pressure (BP) as well as electrocardiographic indices, including heart rate (HR), PR interval, QRS duration, corrected QT (QTc) interval, and ST-T changes were recorded before consumption of a caffeine-containing energy drink and at the specific time points over a 4-h test duration. RESULTS: We found statistically significant HR decline (p=0.004) and more frequent ST-T changes (p=0.004) after the participants consumed the energy drink. However, readings for systolic BP (p=0.44), diastolic BP (p=0.26), PR interval (p=0.449), QRS duration (p=0.235), and QTc interval (p=0.953) showed no significant change post-consumption. CONCLUSION: In conclusion, we demonstrated that the consumption of energy drinks could contribute to HR decline and ST-T change in healthy young adults.

Synthesis and molecular modeling of six novel monastrol analogues: evaluation of cytotoxicity and kinesin inhibitory activity against HeLa cell line.

BACKGROUND AND THE PURPOSE OF THE STUDY: A common approach in cancer chemotherapy is development of drugs that interrupt the mitosis phase of cell division. Dimethylenastron is a known kinesin inhibitor. In this study, six novel dimethylenastron analogues (4a-f), in which 3-hydroxyphenyl substituent has been replaced with substituted benzylimidazolyl, were synthesized through Biginelli reaction. METHODS: Six novel Biginelli compounds (4a-f) were synthesized through one step Biginelli reaction of imidazole aldehydes (3a-c), dimedone and urea or thioura. In vitro cytotoxicities of prepared compounds were investigated using MTT assay. Furthermore the ELIPA kit was implemented to study inhibitory effects of synthesized compounds on ATPase activity of kinesin by measuring of organic phosphate. RESULTS: Our results indicated that analogue 4c is the most toxic and analogues 4f, 4b and dimethylenasteron were less cytotoxic in compare with other analogues. On the other hand, analogue 4a, 4b, 4c and 4e showed stronger Kinesin inhibition as compared with analogue 4f and dimethylenasteron. None of synthesized compounds were as potent kinesin inhibitor as Taxol. Docking analysis revealed that hydrogen bond formation and hydrophobic interactions were the key factors affecting inhibitory effects of these compounds. CONCLUSION: Newly synthesized compounds were found to have moderate to good cytotoxicity against HeLa cancer cell. Our results may be helpful in further design of dihydropyrimidine as potential anticancer agents.